Obesity is very prevalent among the Pima Indians and represents a major risk factor for insulin resistance and the development of NIDDM. Obesity is a condition of excess body fat and seems to be genetically determined. Our search for the causes of obesity in the Pima population has identified four known familial metabolic parameters predicting body weight gain: a low metabolic rate, a high respiratory quotient (low fat/carbohydrate oxidation ratio), insulin sensitivity, and a low spontaneous physical activity. We are therefore investigating the causes of the variability of these metabolic parameters: 1) females have lower metabolic rate and lower fat oxidation than males, even after adjusting for differences in body size and composition; 2) age is not a major determinant of sedentary energy expenditure, but is associated with lowering of physical activity in free-living conditions; 3) metabolic rate seems to be regulated to maintain a genetically determined body temperature and Pima Indians have lower a sleeping body temperature than Caucasians; and 4) sympathetic nervous system (SNS) activity, measured by micronerve recording is lower in Pima Indians than in Caucasians. In response to spontaneous overfeeding, carbohydrate and protein stores are closely controlled whereas increased fat intake does not result in increased fat oxidation. This has led us to study possible mechanisms regulating fat oxidation: 1) skeletal muscle lipoprotein lipase (LPL) activity correlated inversely with 24-hour respiratory quotient, indicating that a low skeletal muscle LPL activity might cause decreased fatty acid uptake and oxidation; 2) differences in muscle fiber types account for part of the interindividual variability in energy metabolism. These new observations suggest that muscle might be the site of differences in fat utilization which might predispose to obesity.